ArticleHuman molecular genetics2018
tp53-dependent and independent signaling underlies the pathogenesis and possible prevention of Acrofacial Dysostosis-Cincinnati type.
Article in Human molecular genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 29 citations in OpenAlex.
- The Nucleolus in Human Disease: Ribosome Biogenesis, Nucleolar Surveillance, and Therapeutic Opportunities.Biomolecules · 2026Review
- RNA Polymerase III subunit Polr3a is required for craniofacial cartilage and bone development in zebrafish.PLoS genetics · 2026Article
- Early ultraviolet exposure disrupts late dorsal fin skeletal development in zebrafish.Developmental dynamics : an official publication of the American Association of Anatomists · 2026Article
- Ribosomal modifications are associated with mesenchymal fate selection in the neural crest lineage.Nature communications · 2026Article
- NR6A1 is essential for neural crest cell specification, formation and survival.Nature communications · 2026Article
- Gene-environment interactions modulate the phenotype severity in mouse models of congenital craniofacial syndromes.The Journal of clinical investigation · 2025Article
- Mechanisms of ribosomopathy and phase separation-related ribosomopathy.Journal of Zhejiang University. Science. B · 2025Review
- rRNA transcription is integral to phase separation and maintenance of nucleolar structure.PLoS genetics · 2023Article
- POLR1A variants underlie phenotypic heterogeneity in craniofacial, neural, and cardiac anomalies.American journal of human genetics · 2023Article
- Ribosome biogenesis and function in development and disease.Development (Cambridge, England) · 2023Review
- RNA Polymerases I and III in development and disease.Seminars in cell & developmental biology · 2023Review
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- Dynamic regulation and requirement for ribosomal RNA transcription during mammalian development.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Nucleolin loss of function leads to aberrant Fibroblast Growth Factor signaling and craniofacial anomalies.Development (Cambridge, England) · 2022Article
- Zebrafish as model for studies in dentistry.Journal of orthodontic science · 2022Review
- Structure of the human RNA polymerase I elongation complex.Cell discovery · 2021Article
- Zebrafish Models for Human Skeletal Disorders.Frontiers in genetics · 2021Review
- Paired Box 9 (PAX9), the RNA polymerase II transcription factor, regulates human ribosome biogenesis and craniofacial development.PLoS genetics · 2020Article
- EFTUD2 gene deficiency disrupts osteoblast maturation and inhibits chondrocyte differentiation via activation of the p53 signaling pathway.Human genomics · 2019Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Ribosome biogenesis is a global process required for growth and proliferation in all cells, but disruptions in this process surprisingly lead to tissue-specific phenotypic disorders termed ribosomopathies. Pathogenic variants in the RNA Polymerase (Pol) I subunit POLR1A cause Acrofacial Dysostosis-Cincinnati type, which is characterized by craniofacial and limb anomalies. In a zebrafish model of Acrofacial Dysostosis-Cincinnati type, we demonstrate that polr1a-/- mutants exhibit deficient 47S rRNA transcription, reduced monosomes and polysomes and, consequently, defects in protein translation. This results in Tp53-dependent neuroepithelial apoptosis, diminished neural crest cell proliferation and cranioskeletal anomalies. This indicates that POLR1A is critical for rRNA transcription, which is considered a rate limiting step in ribosome biogenesis, underpinning its requirement for neuroepithelial cell and neural crest cell proliferation and survival. To understand the contribution of the Tp53 pathway to the pathogenesis of Acrofacial Dysostosis-Cincinnati type, we genetically inhibited tp53 in polr1a-/- mutant embryos. Tp53 inhibition suppresses neuroepithelial apoptosis and partially ameliorates the polr1a mutant phenotype. However, complete rescue of cartilage development is not observed due to the failure to improve rDNA transcription and neural crest cell proliferation. Altogether, these data reveal specific functions for both Tp53-dependent and independent signaling downstream of polr1a in ribosome biogenesis during neural crest cell and craniofacial development, in the pathogenesis of Acrofacial Dysostosis-Cincinnati type. Furthermore, our work sets the stage for identifying Tp53-independent therapies to potentially prevent Acrofacial dysostosis-Cincinnati type and other similar ribosomopathies.
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